Efficacy of Pharmacotherapy

® Each antidepressant has a response rate of approximately 60% to 80%, and no antidepressant medication or class has been reliably shown to be more efficacious 7,21

than another. MAOIs may be the most effective therapy for atypical depression, but MAOI use continues to wane because of problematic adverse effects, dietary and

21 28

drug restrictions, and possibility of fatal drug interactions. ' There is some evid ence that dual-action antidepressants, such as TCAs and SNRIs, may be more effective for inpatients with severe depression than are the single-action drugs such as SSRIs,21,28 but the more general assertion that multiple mechanisms of action confer efficacy advantages is quite controversial.

Selection of Medication

Figure 38-1 depicts a well-known algorithm for the pharmacologic treatment of non-psychotic MDD—the Texas Medication Algorithm Project.34 Notable aspects of this algorithm include the preferential use of newer antidepressants in the earlier stages of treatment and sequential trials of antidepressant monotherapy prior to the use of combination therapy (see Managing Partial Response or Nonresponse). It has been shown that patients undergoing treatment guided by this algorithm fared better than those who received treatment not guided by the algorithm during a 1-year period, as measured by clinician-rated symptoms, self-reported symptoms, and overall mental func-

tioning. Antipsychotic medication should be combined with antidepressant medication in cases of depression with psychotic features.16

Various factors must be taken into account when selecting antidepressant therapy for a particular patient. The most reliable predictor of response is the patient's history of response (e.g., efficacy, side effects, and overall satisfaction) to antidepressants. To a lesser extent, the history of a first-degree relative's response to antidepressants may be used to predict a patient's response. Adverse-effect profiles should be considered because compliance is influenced greatly by tolerability. In this regard, a frank discussion should occur with the patient in order to determine which adverse effects are acceptable and which are not and how to deal with side effects (i.e., using chewing gum, hard candy, or ice chips for dry mouth). The clinician must be careful to contemplate potential drug-drug interactions and disease-state interactions. For instance, a patient with seizure disorder would be an inappropriate candidate for bupropion therapy. The presence of comorbid psychiatric conditions can help the clinician to determine the best antidepressant to choose for a patient. For example, an SSRI can treat both MDD and panic disorder, obviating the need for separate medication therapy. The patient must be willing and able to comply with dosing schedules (e.g., upward titration of TCAs or twice-daily dosing of nefazodone) and special instructions (e.g., dietary restrictions with MAOI therapy) associated with certain antidepressants. Another patient-specific factor is the potential for accidental or intentional overdosing because certain antidepressants (e.g., TCAs) are quite toxic and potentially lethal in overdose situations. Finally, the patient should be able to comfortably afford the

chosen medication or else compliance is at risk. Time Course of Response

Unfortunately, antidepressants do not produce a clinical response immediately. Improvement in physical symptoms, such as sleep, appetite, and energy, can occur within the first week or so of treatment. Although a recent metaanalysis suggests earlier effects of antidepressant treatment,36 it is widely accepted that approximately 2 to 4 weeks of treatment are required before improvement is seen in emotional symptoms of depression, such as sadness and anhedonia. Furthermore, as long as 6 to 8 weeks

7 21 23

of treatment may be required to see the full effects of antidepressant therapy. ' ' Managing Partial Response or Nonresponse

Approximately one-third of patients with MDD do not respond satisfactorily to their

first antidepressant medication. In such cases, the clinician must evaluate the adequacy of antidepressant therapy, including dosage, duration, and patient compliance. 7 Treatment reappraisal should also include verification of the patient's diagnosis and reconsideration of clinical factors that could be impeding successful therapy, such as concurrent medical conditions (e.g., thyroid disorder), comorbid psychiatric conditions (e.g., alcohol abuse), and psychosocial issues (e.g., marital stress).16

A series of reports from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial revealed that remission is associated with a better overall prognosis for patients than is improvement alone. STAR*D also established that in patients with a greater level of resistance, clinicians are less likely to push the patient to achieve remission, and in addition, those patients with the greatest levels of resistance had the highest rates of relapse. In these cases, STAR*D established some successful

treatment recommendations.

For patients who have experienced a partial response, extending the medication trial and/or using higher doses within the recommended dosage range of the antide-pressant may be helpful.16 Another option is to employ augmentation therapy, that is,

adding another medication that generally is not used as an antidepressant. Augmenting agents with clear efficacy include lithium and triiodothyronine, whereas initial enthusiasm has lessened to some extent for the serotonergic drugs buspirone and pindo-

3o lol owing to negative findings in controlled trials. Aripiprazole, a second-generation antipsychotic was recently FDA approved for augmenting partial response to antide-

pressants. Efficacy has been suggested for dopaminergic drugs (e.g., pramipexole), psychostimulants (e.g., methylphenidate), and atypical antipsychotics (e.g., olanzapine), whereas various other medications such as anticonvulsants (e.g., valproic acid),

modafanil, and estrogen have anecdotal evidence to support their use. A third option is to make use of combination therapy, whereby another antidepressant, typically from a different pharmacologic class, is added to the first antidepressant medication. Examples include combining bupropion and SSRIs and combining TCAs and SSRIs.39,40

Switching to a different antidepressant is a common strategy for patients who have had no response to initial antidepressant therapy but also is acceptable in cases of partial response.16 Relative to augmentation/combination, advantages of switching include improved compliance, decreased costs, and less concern over drug-drug interactions, whereas disadvantages include loss of time ("reset the clock") and loss of any improvement seen with the initial drug.40 When switching from one antidepressant to another, clinicians may choose to stay within the same class (e.g., sertraline to fluoxetine) or go outside of the class (e.g., paroxetine to venlafaxine). ,40


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FIGURE 38-1. Strategies for the treatment of nonpsychotic major depression. Redrawn with permission from the Texas Medication Algorithm Project. (AD, antidepressant; BUP, Bupropion; BUS, Buspirone; ECT, electroconvulsive therapy; Li, lithium; T3, liothyronine; LTG, lamotrigine; MAOI, monoamine oxidase inhibitor; MOA, Mechanism of action; MRT, Mirtazapine; OLZ, Olanzapine; RSP, risperidone; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; VNS, vagus nerve stimulation.

Nonpharmacologic interventions in cases of treatment nonresponse include adding or changing to psychotherapy or initiating ECT.16

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